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bioRxiv · 10.64898/2026.05.21.726965

The Q226H Mutation in Avian H5N1 Hemagglutinin Mediates a Path towards Structural Adaptation in Humans

Edwards, R. A.·Adu, O. F.·Tchesnokov, E. P.·Kocincova, D.·Woolner, E.·Turner, Z.·Bui, D. T.·Mahal, L. K.·Zelyas, N.·Klassen, J. S.·Drabovich, A. P.·Das, K.·Gotte, M.
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Abstract

The global outbreak of highly pathogenic avian influenza (HPAI) A(H5N1) among birds and the spillover to mammals increases the risk for humans. A recent case in British Columbia with a clade 2.3.4.4b H5 virus infection revealed a mixture of 226Q/H in the receptor-binding site of hemagglutinin. While significant changes in pre-existing immunity by H1 or H3 polyclonal sera are not evident, we show that the Q226H mutation enables binding to human-type a2-6 sialic acid receptors. High-resolution cryo-EM structures provide a basis for the alteration in receptor preference and show that a possible path towards human adaptation also requires a conformational change of the bound a2-6-sialylated glycan. Continued surveillance for additional mutations that could enhance this phenotype is warranted.

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Edwards, R. A., Adu, O. F., Tchesnokov, E. P., Kocincova, D., Woolner, E., Turner, Z., Bui, D. T., Mahal, L. K., Zelyas, N., Klassen, J. S., Drabovich, A. P., Das, K., Gotte, M.. 2026-05-26. The Q226H Mutation in Avian H5N1 Hemagglutinin Mediates a Path towards Structural Adaptation in Humans. https://doi.org/10.64898/2026.05.21.726965

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